The alphaviruses and flaviviruses are two groups of mosquito-borne viruses cause many cases of human illness each year. We wish to understand the molecular biology of the replication of these two groups of viruses in great detail and to explore the evolution of these viruses. Three specific aims are proposed in this renewal application. (1) To identify and characterize the cellular receptor to which alphaviruses attach in the primary process of infection. Alphaviruses have a broad phylogenetic host range, replicating in anthropods (mosquitoes) as well as in higher vertebrates, and the distribution of cellular receptors and the possible involvement of receptors in tissue tropism and virulence will be explored. (2) To explore the interactions of the nucleocapsid and envelope glycoproteins of alphaviruses with one another during the maturation of alphaviruses. Site specific mutagenesis will be used to examine domains of capsid and domains of glycoproteins that have been implicated in previous results as important in these interactions. Second site revertants of site specific mutants may also be useful in defining domains that interact. (3) To determine the translation strategy and processing mechanisms used to product flavivirus proteins. From sequencing data both virus encoded and cellular proteases have been invoked in processing of a very large precursor flavivirus polyprotein. Translation of RNAs derived from cDNA constructs in vivo or in vitro will be used in these studies.